Randomized controlled trial of an oral gastrin receptor antagonist for the treatment of postmenopausal osteoporosis

High gastrin levels may help explain the association between several conditions and osteoporosis, such as pernicious anaemia, the use of proton pump inhibitors, and atrophic gastritis. This study aimed to determine whether administering a gastrin receptor antagonist (GRA) to older women would lower their bone turnover markers and, therefore, be a suitable preventive measure for osteoporosis. We conducted a randomised, double-blind, placebo-controlled clinical trial to assess the efficacy, safety, and tolerability of an oral GRA (netazepide) 100 mg administered daily for 90 days in postmenopausal women. Our primary endpoint was the change in the bone turnover marker (BTM) plasma CTX (automated immunoassay analyser) at days 0, 7, 28, 56, and 90. We also measured other BTMs, and gastrin and group I pepsinogens (ELISA assays). We studied the effect of the drug on the log-transformed baseline scaled ratio for bone turnover marker and gastric markers using mixed-model ANOVA for the fixed effects of treatment, time, and the treatment-by-time interaction, with the baseline value included as a covariate. We studied 99 women, with a mean age of 60 years and BMD T- scores for the spine and total hip of -0.96 and -0.09, respectively. We found that gastrin increased by 90% in response to GRA as early as 7 days (p-value for treatment 0.0008), and group I pepsinogens decreased by 15% as early as 7 days (p-value 0.0002). There was no significant change in plasma CTX. A high percentage of women (81/99) completed the study, and the GRA was well tolerated. GRA had the expected effects on the gastric markers with an increase in gastrin and a decrease in group I pepsinogens. However, the absence of any change in the bone resorption marker plasma CTX was a bit surprising. Based on this study it appears that short term gastrin receptor antagonism is unlikely to be a successful strategy in the prevention of osteoporosis. However, this a preliminary exploration of a novel hypothesis and larger studies might be needed.